Patient-specific tumor neoantigen peptide–Major Histocompatibility Complex (Neoantigen-pMHC)

Patient-specific tumor neoantigen peptide–Major Histocompatibility Complex (pMHC) complexes are unique molecular targets formed when mutated proteins within a tumor are processed and presented on the cell surface by Human Leukocyte Antigen (HLA) molecules [1][2]. These neoantigens arise from somatic mutations, such as single nucleotide variants or frameshifts, and are absent from healthy tissues, providing a high degree of tumor specificity and reducing the risk of autoimmune cross-reactivity [3]. Recognition of these complexes by the T-cell receptors (TCRs) of Tumor-Infiltrating Lymphocytes (TILs) or engineered TCR-T cells triggers a potent cytotoxic immune response against the cancer cells [4]. Because these targets are highly individualized, they form the basis for personalized immunotherapy approaches, including NeoTIL cell therapy and neoantigen-based mRNA vaccines [5]. However, the therapeutic application is challenged by the high degree of inter-patient variability and the potential for tumors to escape immune detection through the downregulation of MHC molecules [6]. (Citations: [1] Schumacher & Schreiber, Science 2015; [2] Blass & Ott, Nat Rev Clin Oncol 2021; [3] Gubin et al., Nature 2015; [4] Rosenberg & Restifo, Science 2015; [5] Sahin & Türeci, Science 2018; [6] Garrido et al., OncoImmunology 2016).

Other names

Tumor-specific neoantigen-MHC complexNeoepitope-HLA complexPatient-specific neoantigenTumor-specific antigen (TSA) complexNeoantigen-pMHC

T-cell receptor (TCR) binding to the patient-specific neoantigen-pMHC complex triggers the formation of an immunological synapse, leading to the release of perforin and granzymes and subsequent cytotoxic lysis of the tumor cell.